Respiratory channelopathies Flashcards
How many people are carriers of the CFTR gene mutation
1 in 20
What organs are affected by cystic fibrosis
Airways - clogging and infection
Liver - blockage of bile ducts, liver function problems
Pancreas - blockage of ducts prevents secretion of digestive enzymes
Small intestine - Obstructions due to thick content
Reproductive tract - Absence of a vas deferens
Skin - excess secretion of NaCl via sweat glands
What does CFTR stand for
Cystic fibrosis transmembrane conductance
How many TMDs does CFTR have
12
What mediates the opening and closing of the channel
Phosphorylation of the regulatory region
Where does ATP bind the channel
NBD1/NBD2 regions
What is the most common mutation
Delta F508 mutation
What 5 processes do CFTR mutations impact on
- Production -
- Processing - The protein is misfolded so is sent for degradation instead of being processed
- Trafficking - Processed but not moved to the plasma membrane
- Regulation - The channel doesn’t open as much as it should
- Conductance - The pore itself doesn’t allow chloride ions through
What is the normal airway model for CFTR
Chloride accumulates in the cell due to the action of NKCC1
CFTR opens driving Cl into the apical solution as well as water
This is balanced by the inward movement of Na via ENAC, able to work due to inward gradient created by NaKATPase.
This drives sodium and water reabsorption which dehydrates the apical solution
If one channel is more active - the other channel becomes less active
What is the optimum width for the airway surface liquid layer
7um - cilia beat most efficiently at this width in order to remove mucous
How does the lung physiology change in a sufferer of cystic fibrosis
No functional CFTR so no chloride secretion - Na reabsorption still occurs
Lack of CFTR means no inhibition of ENaC so too much Na reabsorption coupled with water reabsorption dehydrate the airway surface liquid layer
The cilia then bend over and can’t beat efficiently so there isn’t much movement in the liquid or the mucous that sits above it
Is DeltaF508 mutation functional
Yes - misfolded so doesn’t make it to the membrane - but using a chaperone protein to get it there it does have some functionality
How does cystic fibrosis give colonic protection and how did this lead to such a high incidence of CF carriers
Crypt cells in the lumen of the colon
Lower 2/3rds of the crypt cells have CFTR channels so secrete water into the lumen creating moist faeces
In cholera patients - enterotoxins cause excess CFTR stimulation - causes diarrhea
In CF carriers this has a reduced effect as there are less CFTR channels so less likely to die of dehydration - more carriers survived when cholera was such a large problem
How do read through agents affect CFTR
Forces production of CFTR in cases where they would normally be prevented through nonsense or truncation mutations
How do correctors affect mutant CFTR
Forces mutant CFTR to the cell membrane - if the mutant channel has some functionality chloride secretions is restored
